Process for preparing alkyl 3-alkyl-isoxazole-5-carboxylate



United States Patent 3 196,161 Pnocnss son rnnrannvo ALKYL 3-ALKYL- ISOXAZULE-S-CARB OXY LATE Kunio Nakagawa, Hyohgo Prefecture, and Shinzaburo Sumimoto, Gsaira Prefecture, Japan, assignors to Shionogi & (30., Ltd, Osaka-ski, Japan No Drawing. Filed June 26, 1962, Ser. No. 205,189 Qlaims priority, application Japan, Nov. 20, 1959, 34/36,484 3 Claims. (Cl. 260-307) This application is a continuation-in-part of copending application Serial No. 70,372 filed November 21, 1960 (now abandoned).

The present invention relates to a process for preparing alkyl 3-alkylisoxazole-S-carboxylate. More particularly, it relates to an improvement in the production of alkyl 3-alkylisoxazole-S-carboxylate which is useful as a starting material in the synthesis of monoamine oxidase inhibitors.

The said isoxazole compound has been heretofore produced by condensing alkyl acylpyruvate with hydroxylamine in acidic aqueous medium at a low temperature and refluxing the resulting 3-alkylisoxazole-S-carboxylic acid in alcoholic medium in the presence of an acid [Meltzer et al.: I. Am. Pharm. Assoc, 42, 594 (1953)]. The process, however, yields a mixture of alkyl -3-alkylisoxazole-S-carboxylate and its position isomer, i.e., alkyl 5 alkylisozazole 3 carboxylate, in each considerable amounts. Therefore, the process is not an economical method for the production of alkyl 3-allryl-isoxazole-5- carboxylate. Furthermore, it is very difiicult to separate the two isomers from a mixture thereof by an ordinary operation such as solvent extraction and distillation, because their properties are very similar to each other. This difiiculty is undesirable in view of the use of the said isoxazole compound as a starting material in the manufacture of a medicinal which is especially required to be pure. However, the above defects have been now overcome by the process of the present invention which produces selectively alkyl 3-alkyl-isoxazole-5-carboxylate as a main product.

Accordingly, an object of the present invention is to provide a commercial process for producing alkyl 3-alkylisoxazole-S-carboxylate in a'good yield with a high purity. This and other objects and the manner in which they are accomplished will become apparent to those conversant with the art from the following description of the general class of compounds and the several specific examples and methods of obtaining them presented.

The process of the present invention includes two main reactions, i.e., addition and cyclization, and one side reaction, i.e., hydrolysis, and it is representable by the following scheme:

"Ice

With respect to the above scheme, the following facts have been now discovered by the inventors:

(l) The addition reaction is reversible. The equilibrium between the 'y-oxine II and the a-oxime II through alkyl acylpyruvate I is affected by some reaction conditions. Thus, the equilibrium is mostly affected by the acidity of the reaction medium. It generally proceeds to the left in alkaline or neutral medium and to the right in acidic medium. The equilibrium needs the presence of water which is inclined to move it to the left side. The equilibrium is also influenced somewhat by heat and a hi h reaction temperature accelerates its movement to left or right.

(2) The cyclization reaction is not reversible. Both the conversion of the -oxime H into the S-carboxylate III and that of the a-oxime II into the 3-carboxylate III re accelerated under an acidic condition at a high temperature but interrupted under a neutral or alkaline condition at a low temperature. However, the latter conversion is difiicultly influenced by these conditions in general and sometimes proceeds so fast, subsequent to the addition reaction, that the isolation of the a-oxime H is impossible. On the contrary, the former conversion is greatly influenced by said conditions and, therefore, the -oxime II can be readily obtained under a suitably controlled condition.

(3) The hydrolysis reaction is reversible. Both the equilibrium between the S-carboxylate III and the S-carboxylic acid IV and that between the 3-carboxylate III and the 3-carboxylic acid IV are moved downwards in the presence of water and upwards in the presence of alkanol. These movements are accelerated by heat.

The process of the present invention is based on these discoveries and substantially comprises reacting alkyl acylpyruvate I with hydroxylamine in a neutral or alkaline aqueous medium, heating the resulting 'y-oxime II in an acidic anhydrous medium and recovering the produced S-carboxylate Hi from the reaction mixture.

The first step is concerned with the addition reaction. In this step, the starting materials are alkyl acylpyruvate corresponding to formula I and hydroxylamine. Hydroxylamine is usually employed in the form of salt Such as hydroxylarnine hydrochloride (H NOHHCI, hydroxyl amine sulfate (H NOHJ/2H SO and hydroxylamine hydrogen sulfate (H NOHH SOQ at the ratio of 1 to 1.3 moles of salt to 1 mole of alkyl acylpyruvate I. As the reaction solvent, there may be employed water or its mixture with a water-miscible inert solvent such as methanol and ethanol. Prior to the reaction, the reaction medium should be neutralized or alkalized by an alkaline substance such as sodium hydroxide and potassium hydroxide. The reaction is exothermic and can proceed automatically without any regulation of the reaction temperature in 30 minutes to 2 hours. t

The second step is concerned with the cyclization reaction. Although the 'y-oxime II produced in the first step may be subjected to the cyclization reaction with or Without the previous separation from the reaction mixture, the previous separation is preferred for the simplification of the operation in the second step. The separation may be accomplished according to a per se conventional manner such as solvent extraction and distillation. The cyclization reaction can be carried out by heating the isolated 'y-oxime II in the presence of an acid such as cone. sulfuric acid and cone. hydrochloric acid in an anhydrous inert organic solvent such as methanol, ethanol, benzene, toluene and xylene at a temperature from 60 to C. The thus-produced S-carboxylate III can be readily recovered from the resultant mixture by a per se conventional method. When the 'y-oxime II is employed in this step without the separation from the reaction mixture in the first step, the said reaction mixture may be rendered acidic by the addition of an acid such as sulfuric acid and hydrochloric acid and then heated. In this case, however, there may be present a considerable amount of Water, which causes the undesirable hydrolysis of the once-produced S-carboxylate III to the S-carboxylic acid IV, in the reaction medium. Therefore, it may he sometimes required for the production of the S-carboxylate III in a good yield to heat the acidified mixture while removing water. For attaining this object, the acidified mixture may be refluxed in the presence of a Water-immiscible inert solvent such as benzene, toluene and xylene with azeotropic removal of water. Recovery of the -carboxylate III from the resultant mixture can be readily performed by a per se conventional method such as solvent extraction and distillation.

The products obtained by the process of the present invention may be useful as intermediates in the synthesis of monoamine oxidaseinhibitors. For instance, ethyl 3-methylisoxazole-5-carboxylate (R is methyl and R is ethyl in the Formula III) is employed for the production of 1-benzy1-2-(3-methyl-5-isoxazolylcarbonyl)-hydrazine according to the following scheme:

r ll N Example 1 To a solution of hydroxylamine hydrochloride (35.5 g.) in water (50 ml.), there is added a solution of sodium hydroxide (19.4 g.) in Water (25 ml.), and then ethyl acetylpyruvate (79.0 g.) while stirring. The reaction proceeds with generation of heat. Stirring is continued for 1 hour. After cooling, the reaction mixture is extrated with ether (400 rnl.). The ether extract is washed with water and dried. Removing the ether from the dried ether extract, there is obtained a light yellow crystalline substance (77 g.), which is distilled under reduced pressure to give ethyl (a-hydroxyiminoethyl)-pyruvate (36 g.) as a fraction boiling at 135 to 137 C./6 mm. Hg. It is solidified on cooling to afford crystals melting at 77 to 78 C.

due is shaken with a mixture of water and benzene. The

benzene layer is dried and the solvent is removed. The residual oilis distilled under reduced pressure to yield ethyl 3-methylisoxazole-S-carboxylate as a fraction boiling at 108 to 109 C./12 mm. Hg in a yield of 94.2%. The purity is 95.3%.

Analysis.-Calcd. for CqHgNOg: C, 54.19; H, 5.80; N, 9.03. Found: C, 54.48; H, 6.19; N, 9.39.

4 Example 2 To a solution of hydroxylamine hydrochloride (28.7 g.) in water (37 ml.), there is added a solution of sodium hydroxide (16.0 g.) in water (25 ml.), and then ethyl isobutyroylpyruvate (65.8 g.). The reaction proceeds with generation of heat. Stirring is continued for 1 hour. After cooling, the reaction mixture is extracted with ether. The ether extract is washed with water and dried. Removing the ether from the resulting ether extract, the residue is distilled under reduced pressure'to yield ethyl (a-hydroxyirnino-fl-methylpropyl)-pyruvate (45.28 g.) as a fraction boiling at 118 to 121 C./2.3 mm. Hg.

1d, 1.4622. A552? 208 In (6:3090).

A.nalysis.Calcd. for C H O N: C, 53.73; H, 7.41; N, 6.97. Found: C, 53.71; H, 7.67; N, 6.75.

To a solution of ethyl (a-hydroxyimino-[i-methylpropyl)-pyruvate (10.05 g.) in anhydrous ethanol (14.5 ml.), there is added conc. sulfuric acid (2.54 g.), and the resultant solution is heated for 5 hours at C. Removing the solvent from the reaction mixture, the residue is shaken with a mixture of water and benzene. The benzene layer is dried and the benzene is removed. The residual oil is distilled under reduced pressure to yield ethyl 3-isopropylisoxazole-5-carboxylate (8.56 g.) as a fraction boiling at 82.2 C./2.5 mm. Hg. The purity is 92.8%.

Example 3 To a solution of hydroxylamine hydrochloride (20.1 g.) in water (27 ml.), there is added a solution of sodium hydroxide (11.2 g.) in water (18 ml.), and then ethyl pivaloylpyruvate (50 g.). The reaction proceeds with generation of heat. Stirring is continued for 1 hour. Then, the reaction mixture is treated as in Example 2 to give ethyl (a-hydroxyimino-5,fi-dimethylpropyl)-pyruvate (10.5 g.) as a fraction boiling at 109 to 114 C./ 1.0 mm. Hg.

Analysis.-Calcd. for C10H17O4Nl C, 55.81; H, 7.91; N, 6.51. Found: C, 55.51; H, 8.00; N, 6.88.

To a solution of ethyl (u-hydroxyimino-,B,Bdimethylpropyl)-pyruvate (10.75 g.) in anhydrous ethanol (14.5 ml.), there is added conc. sulfuric acid (2.45 g.), and the resultant solution is heated for 5 hours at 75 C. The reaction mixture is treated as in Example 2 to give ethyl 3-tert.-butylisoxazole-S-carboxylate (9.39 g.) as a fraction boiling at 114 to 116 C./0.6 mm. Hg. The purity is 84.2%.

Example 4 To a solution of hydroxylamine hydrochloride (40.2 g.) in water (53 ml.), there is added a solution of sodium hydroxide (22.4 g.) in water (35 ml.), and then ethyl propionylpyruvate (86.0 g.) While stirring. The reaction proceeds with generation of heat. Stirring is continued for 1 hour. Then, the reaction mixture is treated as in Example 2 to give ethyl (oc-hYdIOXYlIIliHO- propyl)-pyruvate (60.8 g.) as a fraction boiling at 127 to 128.5 C./ 3.0 mm. Hg. It is crystallized from carbon tetrachloride to afford crystals melting at 45.5 to 49 C.

Analysis.Cal cd. for C H NO C, 51.34; H, 6.95; N, 7.49. Found: C, 51.92; H, 7.15; N, 7.41.

To a solution of ethyl (a-hydroxyirninopropyl)-pyruvate (9.35 g.) in anhydrous ethanol (14.5 ml.), there is added conc. sulfuric acid (2.45 g.), and the result-ant solution is heated for 5 hours at 75 C. The reaction mixture is treated as in Example 2 to give ethyl 3-ethylisoxazole-S-carboxylate (8.07 g.) as a fraction boiling at 106 C./6.0 mm. Hg. The purity is 96.1%.

Example 5 The reaction mixture (20.4 g.) from hydroxylamine and ethyl propionylpyruvate in Example 4 is dissolved Example 6 To a solution of hydroxylamine hydrochloride (23.5 g.) in water (31 ml.), there is added a solution of sodium hydroxide (13.0 g.) in water (21 ml), and then ethyl n-butyroylpyruvate (53.9 g.) while stirring. The reaction proceeds with generation of heat. Stirring is continued for 1 hour. Then, the reaction mixture is treated as in Example 2 to give ethyl (OL-hYdI'OXYiHllIlO- n-butyl)-pyruvate (35.02 g.) as a fraction boiling at 123 to 126 C./ 1.8 mm. Hg. It is crystallized from carbon tetrachloride to afford crystals melting at 47 to 48.5 C.

A233? 208 m (ez3580).

Analysis.Calcd. for C H NO C, 53.73; H, 7.46; N, 6.97. Found: C, 54.26; H, 7.62; N, 6.86.

To a solution of ethyl (a-hydroxyimino-n-butyl)-pyruvate (10.05 g.) in anhydrous ethanol (14.5 ml.), there is added conc. sulfuric acid (2.45 g.), and the resultant solution is heated for 5 hours at 75 C. The reaction mixture is treated as in Example 2 to give ethyl 3-npropylisoxazole-S-carboxylate (8.37 g.) as a fraction boiling at 106 to 107 C./4 mm. Hg. The purity is 97.1%.

Example 7 wherein R and R each represents lower alkyl with hydroxylamine in an aqueous solution of a member selected from the group consisting of sodium hydroxide and potassium hydroxide, heating the resulting product with an acid selected from the group consisting of sulfuric acid and hydrochloric acid in an anhydrous inert organic solvent selected from the group consisting of methanol, ethanol, benzene, toluene and xylene at a temperature from 60 to 90 C. and recovering the produced alkyl 3-alkylisoxazole-S-carboxylate having the following formula:

wherein R and R each has the same significance as designated above from the reaction mixture.

2. Process for preparing alkyl 3-alkylisoxazole-5-carboxylate which comprises reacting alkyl acylpyruvate having the following formula:

wherein R and R each represents lower alkyl with hydroxylamine in an aqueous solution of a member selected from the group consisting of sodium hydroxide and potassium hydroxide, recovering the intermediarily produced 'y-oxime having the following formula:

wherein R and R each has the same significance as designated above from the reaction mixture, heating the said 'y-oxime with an acid selected from the group consisting of sulfuric acid and hydrochloric acid in an anhydrous inert organic solvent selected from the group consisting of methanol, ethanol, benzene, toluene and xylene at a temperature from 60 to C. and recovering the pro duced aikyl 3-alkylisoxazole-5-carboxylate having the following formula:

il-Wt \0/ Go0R' wherein R and R each has the same significance as designated above from the reaction mixture.

3. Process for preparing alkyl 3-methylisoxazole-5- carooxylate which comprises reacting alkyl acylpyruvate having the following formula:

CH COCH COCOOR wherein R represents lower alkyl with hydroxylamine in an aqueous solution of sodium hydroxide, recovering the intermediarily produced 'y-oxime having the following formula:

CH3COH2CO-GOOR' wherein R has the same significance as designated above from the reaction mixture, heating the said 'yOXiI11e with sulfur'c acid in anhydrous ethanol at a temperature from 60 to 90 C. and recovering the produced alkyl 3-alkylisoxazole-S-carboxylate having the following formula:

wherein R has the same significance as designated above from the reaction mixture.

References Cited by the Examiner Elderiield, Heterocyclic Compounds, vol. 5 (New York, 1957), pages 454-8 and 470.

Meltzer, Chem. Abstracts, vol. 49, pages 101849 (1955).

Ryan, Chem. Abstracts, vol. 8, page 1107 (1914).

NICHOLAS S. RIZZO, Primary Examiner. 

1. PROCESS FOR PREPARING ALKYL 3-ALKYLISOXAZOLE-5-CAR BOXYLATE WHICH COMPRISES REACTING ALKYL ACYLPYRUVATE HAVING THE FOLLOWING FORMULA:
 2. PROCESS FOR PREPARING ALKYL 3-ALKYLISOAXAZOLE-5-CARBOXYLATE WHICH COMPRISES REACTING ALKYL ACYLPYRUVATE HAVING THE FOLLOWING FORMULA: 